The aims of this grant proposal are: 1) To determine the physiologically important counterregulatory mechanisms responsible for recovery from hypoglycemia in normal man; specifically, we will assess the roles of changes in glucose production and glucose utilization (measured isotopically) and the actions of glucagon, growth hormone, cortisol, adrenomedullary catecholamines, neural norepinephrine, and hepatic autoregulation on these processes. Subcutaneous injection of insulin, rather than intravenous injection or infusion of insulin, will be used to induce hypoglycemia since there is evidence that this model may more accurately reflect the clinical situation. The roles of the factors indicated above will be evaluated by assessing the consequences of pharmacologic blockade of hormone secretion (somatostatin, metyrapone) or action (phentolamine/propranolol) and by assessing changes in glucose production and utilization under conditions in which specific hormone secretion is not possible (e.g., adrenalectomy) or when counterregulation is not stimulated (euglycemic glucose clamp). 2) To characterize and determine the causes of impaired glucose counterregulation in patients with diabetes mellitus; specifically, in addition to identifying the factors important in recovery from hypoglycemia in patients with diabetes (which appear to differ from those of nondiabetic individuals), we will attempt to determine the mechanism(s) responsible for the exaggerated hypoglycemia and posthypoglycemic hyperglycemia that frequently develop in these patients. Further knowledge concerning the defects in glucose counterregulatory mechanisms present in diabetes is needed in view of the growing use of intensified insulin treatment regimens and their associated risk of hypoglycemia. Such knowledge could lead to better selection of patients for these regimens as well as the development of means to diminish the risks for hypoglycemia.